Summary: Current HIV vaccine induced antibody responses are known to generate virus binding antibodies, but a vaccine that generates broadly neutralizing antibodies has yet to be identified. Alternative approaches need to be developed to gain enhanced vaccine function by optimizing the effector functions of the antibodies generated. Through antibody-cell surface mucin interactions, the antibodies would facilitate trapping of HIV before it could reach and interact with underlying columnar epithelial cells, which would effectively neutralize the virus. We have identified a specific interaction between a cell-associated mucin, MUC16, and IgG. This interaction appears to be an effector function regulated during the immune response because 1) the interaction between IgG and MUC16 is increased during chronic HIV infection, 2) the MUC16 associating IgGs are enriched for binding to gp41, but not gp120, and 3) the MUC16 associating IgGs are depleted for ADCC activity. In the proposed work, we will dissect and define the interaction between MUC16 and IgG, define the ability of MUC16 to trap HIV via antibody specific interactions, and identify immune responses that are optimal for directing vaccine induced antibodies to increase MUC16-IgG interactions. Exploring the interaction of antibody-mucin interactions to enhance vaccine function represents an excellent opportunity to tune and optimize current vaccines to prevent acquisition. Importantly, MUC16 covers the columnar epithelium of the upper female reproductive tract and the digestive tract. Enhancing barrier function of these mucosal sites of HIV transmission with a vaccine induced antibody response could prove to increase the efficacy of current vaccine regimens. Knowing which type of IgG subtype(s) and glycoform(s) are involved in MUC16 association could also become an important aspect of vaccine development. For example, different adjuvants, delivery systems, and vaccination regimens could be considered for optimal mucin interacting antibody responses in small trials. This information could inform challenge studies in rhesus macaques and then eventually in a large clinical trial.